miR‐181a/b downregulation: a mutation‐independent therapeutic approach for inherited retinal diseases
Abstract Inherited retinal diseases (IRDs) are a group of diseases whose common landmark is progressive photoreceptor loss. The development of gene‐specific therapies for IRDs is hampered by their wide genetic heterogeneity. Mitochondrial dysfunction is proving to constitute one of the key pathogeni...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2022-11-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202215941 |
| _version_ | 1797287834504134656 |
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| author | Sabrina Carrella Martina Di Guida Simona Brillante Davide Piccolo Ludovica Ciampi Irene Guadagnino Jorge Garcia Piqueras Mariateresa Pizzo Elena Marrocco Marta Molinari Georgios Petrogiannakis Sara Barbato Yulia Ezhova Alberto Auricchio Brunella Franco Elvira De Leonibus Enrico Maria Surace Alessia Indrieri Sandro Banfi |
| author_facet | Sabrina Carrella Martina Di Guida Simona Brillante Davide Piccolo Ludovica Ciampi Irene Guadagnino Jorge Garcia Piqueras Mariateresa Pizzo Elena Marrocco Marta Molinari Georgios Petrogiannakis Sara Barbato Yulia Ezhova Alberto Auricchio Brunella Franco Elvira De Leonibus Enrico Maria Surace Alessia Indrieri Sandro Banfi |
| author_sort | Sabrina Carrella |
| collection | DOAJ |
| description | Abstract Inherited retinal diseases (IRDs) are a group of diseases whose common landmark is progressive photoreceptor loss. The development of gene‐specific therapies for IRDs is hampered by their wide genetic heterogeneity. Mitochondrial dysfunction is proving to constitute one of the key pathogenic events in IRDs; hence, approaches that enhance mitochondrial activities have a promising therapeutic potential for these conditions. We previously reported that miR‐181a/b downregulation boosts mitochondrial turnover in models of primary retinal mitochondrial diseases. Here, we show that miR‐181a/b silencing has a beneficial effect also in IRDs. In particular, the injection in the subretinal space of an adeno‐associated viral vector (AAV) that harbors a miR‐181a/b inhibitor (sponge) sequence (AAV2/8‐GFP‐Sponge‐miR‐181a/b) improves retinal morphology and visual function both in models of autosomal dominant (RHO‐P347S) and of autosomal recessive (rd10) retinitis pigmentosa. Moreover, we demonstrate that miR‐181a/b downregulation modulates the level of the mitochondrial fission‐related protein Drp1 and rescues the mitochondrial fragmentation in RHO‐P347S photoreceptors. Overall, these data support the potential use of miR‐181a/b downregulation as an innovative mutation‐independent therapeutic strategy for IRDs, which can be effective both to delay disease progression and to aid gene‐specific therapeutic approaches. |
| first_indexed | 2024-03-07T18:40:20Z |
| format | Article |
| id | doaj.art-5ffcd1e1e6b74894ad6d8849c7cb89e8 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T18:40:20Z |
| publishDate | 2022-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-5ffcd1e1e6b74894ad6d8849c7cb89e82024-03-02T03:59:55ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-11-011411n/an/a10.15252/emmm.202215941miR‐181a/b downregulation: a mutation‐independent therapeutic approach for inherited retinal diseasesSabrina Carrella0Martina Di Guida1Simona Brillante2Davide Piccolo3Ludovica Ciampi4Irene Guadagnino5Jorge Garcia Piqueras6Mariateresa Pizzo7Elena Marrocco8Marta Molinari9Georgios Petrogiannakis10Sara Barbato11Yulia Ezhova12Alberto Auricchio13Brunella Franco14Elvira De Leonibus15Enrico Maria Surace16Alessia Indrieri17Sandro Banfi18Telethon Institute of Genetics and Medicine (TIGEM) Pozzuoli ItalyTelethon Institute of Genetics and Medicine (TIGEM) Pozzuoli ItalyTelethon Institute of Genetics and Medicine (TIGEM) Pozzuoli ItalyTelethon Institute of Genetics and Medicine (TIGEM) Pozzuoli ItalyTelethon Institute of Genetics and Medicine (TIGEM) Pozzuoli ItalyTelethon Institute of Genetics and Medicine (TIGEM) Pozzuoli ItalyTelethon Institute of Genetics and Medicine (TIGEM) Pozzuoli ItalyTelethon Institute of Genetics and Medicine (TIGEM) Pozzuoli ItalyTelethon Institute of Genetics and Medicine (TIGEM) Pozzuoli ItalyTelethon Institute of Genetics and Medicine (TIGEM) Pozzuoli ItalyTelethon Institute of Genetics and Medicine (TIGEM) Pozzuoli ItalyTelethon Institute of Genetics and Medicine (TIGEM) Pozzuoli ItalyTelethon Institute of Genetics and Medicine (TIGEM) Pozzuoli ItalyTelethon Institute of Genetics and Medicine (TIGEM) Pozzuoli ItalyTelethon Institute of Genetics and Medicine (TIGEM) Pozzuoli ItalyTelethon Institute of Genetics and Medicine (TIGEM) Pozzuoli ItalyMedical Genetics, Department of Translational Medical Science University of Naples “Federico II” Naples ItalyTelethon Institute of Genetics and Medicine (TIGEM) Pozzuoli ItalyTelethon Institute of Genetics and Medicine (TIGEM) Pozzuoli ItalyAbstract Inherited retinal diseases (IRDs) are a group of diseases whose common landmark is progressive photoreceptor loss. The development of gene‐specific therapies for IRDs is hampered by their wide genetic heterogeneity. Mitochondrial dysfunction is proving to constitute one of the key pathogenic events in IRDs; hence, approaches that enhance mitochondrial activities have a promising therapeutic potential for these conditions. We previously reported that miR‐181a/b downregulation boosts mitochondrial turnover in models of primary retinal mitochondrial diseases. Here, we show that miR‐181a/b silencing has a beneficial effect also in IRDs. In particular, the injection in the subretinal space of an adeno‐associated viral vector (AAV) that harbors a miR‐181a/b inhibitor (sponge) sequence (AAV2/8‐GFP‐Sponge‐miR‐181a/b) improves retinal morphology and visual function both in models of autosomal dominant (RHO‐P347S) and of autosomal recessive (rd10) retinitis pigmentosa. Moreover, we demonstrate that miR‐181a/b downregulation modulates the level of the mitochondrial fission‐related protein Drp1 and rescues the mitochondrial fragmentation in RHO‐P347S photoreceptors. Overall, these data support the potential use of miR‐181a/b downregulation as an innovative mutation‐independent therapeutic strategy for IRDs, which can be effective both to delay disease progression and to aid gene‐specific therapeutic approaches.https://doi.org/10.15252/emmm.202215941inherited retinal diseasesmiR‐181mitochondriaphotoreceptortherapy |
| spellingShingle | Sabrina Carrella Martina Di Guida Simona Brillante Davide Piccolo Ludovica Ciampi Irene Guadagnino Jorge Garcia Piqueras Mariateresa Pizzo Elena Marrocco Marta Molinari Georgios Petrogiannakis Sara Barbato Yulia Ezhova Alberto Auricchio Brunella Franco Elvira De Leonibus Enrico Maria Surace Alessia Indrieri Sandro Banfi miR‐181a/b downregulation: a mutation‐independent therapeutic approach for inherited retinal diseases EMBO Molecular Medicine inherited retinal diseases miR‐181 mitochondria photoreceptor therapy |
| title | miR‐181a/b downregulation: a mutation‐independent therapeutic approach for inherited retinal diseases |
| title_full | miR‐181a/b downregulation: a mutation‐independent therapeutic approach for inherited retinal diseases |
| title_fullStr | miR‐181a/b downregulation: a mutation‐independent therapeutic approach for inherited retinal diseases |
| title_full_unstemmed | miR‐181a/b downregulation: a mutation‐independent therapeutic approach for inherited retinal diseases |
| title_short | miR‐181a/b downregulation: a mutation‐independent therapeutic approach for inherited retinal diseases |
| title_sort | mir 181a b downregulation a mutation independent therapeutic approach for inherited retinal diseases |
| topic | inherited retinal diseases miR‐181 mitochondria photoreceptor therapy |
| url | https://doi.org/10.15252/emmm.202215941 |
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